DESCRIPTION: (Applicant's Abstract) The long term goal of this project is to understand the cognitive and neural mechanisms underlying substance abuse. Neurological patients with bilateral ventromedial (VM) lesions of the prefrontal cortex and substance abusers present with similar behavioral characteristics in that 1) they often deny, or they are not aware that they have a problem; 2) they often make the wrong decisions, i.e. when faced with the choice to pursue a course of action that has some immediate reward, at the risk of incurring future negative consequences, including the loss of reputation, job, home, and family, they choose the immediate reward and ignore the future consequences. We hypothesize that substance abusers suffer from a decision-making impairment similar to that of patients with VM lesions. Using a decision-making instrument known as the "Gambling Task", we have made a significant progress in characterizing this impairment in VM patients at the (1 ) behavioral; (2) psychophysiological; and (3) cognitive levels. Here, we plan to apply the experimental strategies we used in the studies of VM patients to study substance abusers. We believe that knowledge about the mechanisms underlying this impairment in VM patients may help us to learn about the cognitive and neural mechanisms underlying substance abuse. Our research approach is promising because 1) the experimental strategies we plan to use have been developed and tested in patients with focal brain lesions; 2) comparing the profiles of the decision-making impairment in patients with focal brain lesions to substance abusers will enable us to link some aspects of the addiction disorder to specific anatomical and cognitive mechanisms. The proposed studies are feasible because 1) preliminary evidence from researchers at NIDA suggests that cocaine abusers show poor performance on the Gambling Task, just like VM patients do; 2) functional neuroimaging studies of human substance abusers show abnormal activity in brain regions that include the VM cortex. In future studies, we will investigate the pharmacological substrates that subserve and influence decision-making in normal individuals and substance abusers. Thus, this research is a beginning that may guide the future development of pharmacotherapeutic strategies that help improve the methods of treatment and prevention of substance abuse.